2-Alkynoic fatty acids display antimycobacterial, antifungal, and pesticidal activities but their antiprotozoal activity has received little attention. In this work we synthesized the 2-octadecynoic acid (2-ODA), 2-hexadecynoic acid (2-HDA), and 2-tetradecynoic acid (2-TDA) and show that 2-ODA is the best inhibitor of the Leishmania donovani DNA topoisomerase IB enzyme (LdTopIB) with an EC50 = 5.3 ± 0.7 μM. The potency of LdTopIB inhibition follows the trend 2-ODA> 2-HDA> 2-TDA, indicating that the effectiveness of inhibition depends on the fatty acid carbon chain length. All of the studied 2-alkynoic fatty acids were less potent inhibitors of the human topoisomerase IB enzyme (hTopIB) as compared to LdTopIB. 2-ODA also displayed in vitro activity against Leishmania donovani (IC50 = 11.0 μM), but it was less effective against other protozoa, Trypanosoma cruzi (IC50 = 48.1 μM) and T. brucei rhodesiense (IC50 = 64.5 μM). The antiprotozoal activity of the 2-alkynoic fatty acids, in general, followed the trend 2-ODA> 2-HDA> 2-TDA. The experimental information gathered so far indicates that 2-ODA is a promising antileishmanial compound.

The first total syntheses of the naturally occurring acetylenic fatty acids 6-heptadecynoic acid (59% overall yield) and 6-icosynoic acid (34% overall yield) was accomplished in four steps. Using the same synthetic sequence the naturally occurring fatty acids (6Z)-heptadecenoic acid (46% overall yield) and (6Z)-icosenoic acid (27% overall yield) were also synthesized. The Δ 6 acetylenic fatty acids displayed good antiprotozoal activity towards Leishmania donovani promastigotes (EC 50 = 1-6 μg/mL), but the 6-icosynoic acid was the most effective in the series. In addition, the (6Z)-icosenoic acid was a much better antiprotozoal compound (EC 50 = 5-6 μg/mL) than the (6Z)-heptadecenoic acid (EC 50 > 25 μg/mL). The saturated fatty acids n-heptadecanoic acid and n-eicosanoic acid were not effective towards L. donovani, indicating that the Δ 6 unsaturation in these fatty acids is necessary for leishmanicidal activity. In addition, both the 6-icosynoic acid and the (6Z)-icosenoic acid were inhibitors of the leishmania DNA topoisomerase IB enzyme (EC 50's = 36-49 μM), a possible intracellular target for these compounds. This is the first study assessing fatty acids as inhibitors of the leishmania DNA topoisomerase IB enzyme.

The fatty acids (±)-2-methoxy-6Z-heptadecenoic acid (1), (±)-2-methoxy-6-heptadecynoic acid (2) and (±)-2-methoxyheptadecanoic acid (3) were synthesized and their inhibitory activity against the Leishmania DNA topoisomerase IB enzyme (LdTopIB) determined. Acids 1 and 2 were synthesized from 4-bromo-1-pentanol, the former in ten steps and in 7% overall yield, while the latter in seven steps and in 14% overall yield. Acid 3 was prepared in six steps and in 42% yield from 1-hexadecanol. Acids 1–3 inhibited the LdTopIB enzyme following the order 2 > 1 ⪢ 3, with 2 displaying an EC50 = 16.6 ± 1.1 μM and 3 not inhibiting the enzyme. Acid 1 preferentially inhibited the LdTopIB enzyme over the human TopIB enzyme. Unsaturation seems to be a prerequisite for effective inhibition, rationalized in terms of weak intermolecular interactions between the active site of LdTopIB and either the double or triple bonds of the fatty acids. Toxicity towards Leishmania donovani promastigotes was also investigated resulting in the same order 2 > 1 > 3, with 2 displaying an EC50 = 74.0 ± 17.1 μM. Our results indicate that α-methoxylation decreases the toxicity of C17:1 fatty acids towards L. donovani promastigotes, but improves their selectivity index.

An activity guided isolation of the H2O subextract of the crude extract of Melampyrum arvense L. afforded iridoid glucosides: aucubin (1), melampyroside (2), mussaenoside (3), mussaenosidic acid (4), 8‐epi‐loganin (5); flavonoids: apigenin (6), luteolin (7), luteolin 7‐O‐β‐glucopyranoside (8); a lignan glycoside dehydrodiconiferyl alcohol 9‐O‐β‐glucopyranoside (9); and benzoic acid (10). β‐Sitosterol (11) and a fatty acid mixture (12) were identified as the active principles of the CHCl3 subextract. The structures of the isolates were elucidated by spectroscopic methods, while the composition of 12 was identified by GC‐MS after methylation. Luteolin (7) appeared as the most active compound against Trypanosoma brucei rhodesiense and Leishmania donovani (IC50 values 3.8 and 3.0 μg/mL). Luteolin 7‐O‐β‐glucopyranoside (8) displayed the best antiplasmodial activity against Plasmodium falciparum (IC50 value 2.9 μg/mL). This is the first detailed phytochemical study on Turkish M. arvense and the first report of the antiprotozoal effect of Melampyrum species and its constituents. Copyright © 2010 John Wiley & Sons, Ltd.

The first total synthesis for the novel fatty acid (±)-2-methoxy-6-icosynoic acid was accomplished in seven steps and in a 14% overall yield starting from 2-(4-bromobutoxy)- tetrahydro-2H-pyran. The title compound displayed an EC50 = 23 ± 1 µM against the human SHSY5Y neuroblastoma cell line and an EC50 = 26 ± 1 µM against the human adenocarcinoma cervix cell line (HeLa) after 48 h of exposure. The corresponding non-methoxylated analog 6- icosynoic acid did not display cytotoxicity (EC50 > 500 µM) towards the studied cell lines as well as the 2-methoxyicosanoic acid (EC50 > 300 µM). The critical micelle concentration (CMC = 20–30 µM) for the (±)-2-methoxy-6-icosynoic acid was also determined. It was found that α- methoxylation decreases the CMC of a fatty acid.